1. Field of the Invention
The present invention pertains to novel excitatory amino acid (EAA) receptor antagonists and particularly to novel, potent and selective antagonists of the N-methyl-D-aspartate (NMDA) subset of EAA receptors having anxiolytic, anticonvulsant, antiepileptic, analgesic, antiemetic, neuroprotective and cognition enhancing actions achieved through the antagonisms of these receptors. In particular, the invention is directed to: .omega.-[2-(tetrazolylalkyl) cyclohexyl-2-aminoalkanoic acids and their interaction with NMDA receptors, their pharmaceutically acceptable salts, and uses thereof.
2. Description of the Prior Art
Excitatory amino acids (EAAs) mediate a substantial portion of the chemical synaptic activity occurring in the central nervous system. Current understanding recognizes at least three major ionotropic receptors for EAAs. Most commonly identified by prototypical agonists, these include:
(1) receptors activated by AMPA [(R,S) -.alpha.-aminomethyl-3-hydroxy-5-methylisoxazolpropionic acid], a cyclic analog of L-glutamate (GLU), (2) receptors recognizing the pyrrolidine neurotoxin kainic acid (KA), and (3) receptors responding to N-methyl-D-aspartate (NMDA), a synthetic analog of L-aspartate [D. R. Curtis, A. W. Duggat, D. Felix, G. A. R. Johnston, A. K. Tebecis and J. C. Watkins, Drain Res., 41, 283-301 (1972); J. C. Watkins and R. H. Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165-204 (1981); A. C. Foster and G. Fagg, Brain Res. Rev., 7, 103-164 (1984)]. In addition to these major ion channel-linked receptors, evidence now suggests the presence of metabotropic EAA receptors which directly activate second messenger systems [D. Schoepp, J. Brockaert and F. Sladeczek, In C. Lodge and G. L. Collinridge (eds.) Tr. Pharmacol Sci., Special Report, "The Pharmacology of Excitatory Amino Acids," Elsevier, Cambridge, UK, pp 74-81 (1991)]. Furthermore, it is now apparent that the NMDA-mediated ionotropic responses are subject to complex regulatory influences and, that this particular recognition site may exist as a supramolecular entity similar to the GABA/benzodiazepine/barbituate effector proteins [E. Costa, Neuropsychophramacology, 2, 167-174 (1989)].
In general, EAA agonists are potent convulsants in an animal model. Additionally, AMPA, KA and the endogenous NMDA agonist, quinolinic acid (QUIN) and the mixed ionotropic/metabotropic against ibotenic acid have been used to produce laboratory models of neurodegenerative disorders [K. Biziere, J. T. Slevin, R. Zaczek, J. S. Collins and J. T. Coyle. In H. Yoshida, Y. Hagihara and S. Ebashi (eds.), "Advances in Pharmacology and Therapeutics," New York: Pergamon, 1982, 271-276; R. Schwarcz, E. O. Whetsell and R. M. Mango, Science, 219, 316-318 (1983)]. It has been suggested for some time that a dysfunction in EAA neurotransmission may contribute to the neuropathology associated with the epilepsies and neurodegenerative conditions [B. Meldrum and M. Williams (eds.), "Current and Future Trends in Anticonvulsant, Anxiety and Stroke Therapy," New York: Wiley Liss, 1990].
The development of selective NMDA antagonists has further expanded the understanding of EAA neurotransmission, physiology and pathophysiology in the mammalian brain. In particular, substantial preclinical evidence is now available suggesting that NMDA receptor antagonists may be useful as anxiolytics, anticonvulsants, antiemetics, antipsychotics or muscle relaxants, and that these compounds may prevent or reduce neuronal damage in instances of cerebral ischemia, hypoxia, hypoglycemia or trauma [R. P. Simon, J. H. Swan, T. Griffiths and B. S. Meldrum, Science, 226, 850-852 (1984); D. N. Stephens, B. S. Meldrum, R. Weldman, C. Schneider and M. Grutzner, Psychopharmacology, 90, 166-169 (1986); D. Lodge and G. L. Collinridge (eds.) "The Pharmacology of Excitatory Amino Acids," Elsevier Trends Journals, Cambridge, UK (1991); A. I. Fader, J. A. Ellison and L. J. Noble, Eur. J. Pharmacol., 175, 165-174 (1990)].
Given the broad therapeutic potential of EAA antagonists, it is not surprising that efforts have been initiated to identify antagonist compounds. The advent of potent and selective antagonists of EAAs, exemplified by .alpha.-amino-.omega.-phosphonoalkylcarboxylic acids has provided a point of departure for the pharmacologic intervention of EAA action at their receptors [J. C. Watkins, Can. J. Physiology Pharmacol., 69, 1064-1076 (1991)]. Although the requisite .omega.-acidic group has most often been a phosphonic acid moiety, recent examples from the literature suggest that a tetrazole functionality can, in some instances, substitute for the phosphono group with a retention of NMDA antagonist activity. Thus, the compounds cis-4-tetrazolylmethyl-piperidine-2-carboxylic acid [P. L. Ornstein, D. E. Schoepp, M. B. Arnold, J. D. Leander, D. Lodge, J. W. Paschal and T. Elzey, J. Med. Chem., 34, 90-97 (1991); P. L. Ornstein et al., U.S. Pat. No. 4,902,687] and decahydro-6-[1(2H)-tetrazol-5-ylmethyl]-3-isoquinolinecarboxylic acid [P. L. Ornstein et al., U.S. Pat. No. 4,902,695] have been reported to be potent and selective NMDA antagonists which are characterized by a shorter duration of action than in the case of the corresponding phosphonic acids. It should be noted that substitution of other monoacidic isosteres for the phosphono acid moiety in similar compounds (e.g., carboxylate or sulfonate) results in abolition of antagonist activity.